Coenzyme Functions

In the cells of mammals (1), there are two different co-enzyme forms of vitamin
B12 (2):

Methylcobalamin

Used by the enzyme methionine synthase to turn homocysteine (HCY) into
methionine. Methionine is further converted to the important methyl donor, S-adenosylmethionine (SAM, aka SAMe) (more info at S-adenosylmethionine (SAMe)).

5'-deoxyadenosylcobalamin

Used by the enzyme methylmalonyl-CoA mutase to convert methylmalonyl-CoA to
succinyl-CoA.

Used by the enzyme leucine aminomutase to convert B-leucine into L-leucine and
vice-versa.

Homocysteine Clearance

Methionine is an essential amino acid provided by the diet. Some methionine is turned into homocysteine.
Homocysteine appears to be a nerve and vessel toxin, promoting cardiovascular disease (CVD) at elevated levels.
HCY is thought to cause CVD by way of oxidative and vessel wall damage (3). The body normally turns
HCY into other molecules, one of which is back into methionine. If this pathway is blocked, HCY levels increase.
Methylcobalamin (B12) is needed by methionine synthase to convert HCY into methionine. Thus, if someone is B12 deficient,
HCY levels will increase.

Anemia, DNA, and Folate

Traditionally, B12 deficiency, normally resulting from the inablity to absorb B12, was diagnosed by finding
abnormally large red blood cells. This sort of anemia has two names:

Macrocytic anemia - when the average
volume of the red blood cells, known as the Mean Corpuscular Volume (MCV), is larger than normal

Megaloblastic anemia - when abnormally large red blood cells are observed under
a microscope

The vitamin folate (aka folic acid) affects the anemia symptoms of B12 deficiency. Folate is needed to
turn uracil into thymidine, an essential building block of DNA (4). DNA is needed for new red blood
cell production and division. B12 is involved in this process because in creating methylcobalamin (used in the
HCY to methionine reaction), B12 produces a form of folate needed to make DNA. If there is no B12 available,
this form of folate can become depleted (known as the methyl-folate trap) and DNA production slows (5).
See Methionine-Homocysteine-Folate-B12 Cycle for an illustration of this pathway.

Only RNA is needed to produce the hemoglobin found in the red blood cells. Unlike DNA, RNA does
not require thymidine. Therefore, if there is not adequate folate, the new red blood cells (which
start out as large cells called reticulocytes) divide slowly, as they are dependent on DNA for
division. At the same time, their hemoglobin is only dependent on RNA and it is produced at a
normal rate. This causes large red blood cells known as macrocytes (4, 6). If
enough of these macrocytes accumulate, the result is macrocytic anemia.

If there are large amounts of incoming folate from the diet, the body does not need to rely on regeneration
of folate from the B12 cycle. Instead, it can use the extra dietary folate to produce DNA, thus preventing
macrocytic anemia (see Methionine-Homocysteine-Folate-B12 Cycle,
bottom right-hand portion). This is why high intakes of folate are said to
"mask" a B12 deficiency.

To add insult to injury, an iron deficiency (which results in small red blood cells from inadequate hemoglobin
synthesis) can counteract the macrocytic cells, making it appear as though the blood cells are normal in the face
of multiple nutritional deficiencies (7).

Intestinal cells are also rapidly dying and being replaced using DNA. A B12 deficiency can make itself
worse because it can prevent the production of the intestinal cells needed to absorb B12.

Traditionally, the existence of macrocytic anemia was relied on to indicate a B12 deficiency. However,
neurological disorders due to B12 deficiency commonly occur in the absence of a macrocytic anemia.

Lindenbaum et al. (8) (1988, USA) examined 141 cases of neurological problems due to B12 deficiency. 40 (28%) had no macrocytic anemia (iron deficiency may have contributed to a lack in 6 patients, and folate therapy could account for 2 others). These 40 had very high serum MMA levels (range: .76-187 µmol/l, 78% > 2 µmol/l) and homocysteine levels (23-289 µmol/l, 45% > 100 µmol/l). Characteristic features of patients with B12 deficiency but without macrocytic anemia included: sensory loss, inability to move muscles smoothly (ataxia), dementia, and psychiatric disorders. They also had borderline (and sometimes normal) B12 levels (see Table 1). One patient died during the first week of treatment, but the other 39 benefited from B12 therapy. Some patients had residual abnormalities after years of treatment.

In a 2011 study from Korea, among 35 patients with vitamin B12 deficiency, most of whom had neurological symptoms, none had anemia (12).

Methylmalonic Acid (MMA)

The second coenzyme form of B12, adenosylcobalamin, takes part in the conversion of
methylmalonyl-CoA to succinyl-CoA. When B12 is not available, methylmalonyl-CoA levels
increase. Methylmalonyl-CoA is then converted to methylmalonic acid (MMA) which then
accumulates in the blood and urine. Since B12 is the only coenzyme required in this pathway,
MMA levels are the best indicators of a B12 deficiency.

In a study of non-vegetarian, older adults with slightly elevated methylmalonic acid (MMA) levels
(.29-3.6 µmol/l), higher sMMA levels did not predict neurological problems (10).
However, these individuals were not compared to people with normal sMMA levels. Because there was no control group,
we cannot say that people with slightly elevated sMMA are not at risk for neurological problems. We can only suggest
that increasing sMMA from .29 to 3.6 may not do any further, measurable neurological harm.